Nonmelanoma Skin Cancer Progression Research Articles

Immune Checkpoints and Cellular Landscape of the Tumor Microenvironment in Non-Melanoma Skin Cancer (NMSC).

Non-melanoma skin cancer (NMSC) is primarily categorized into basal cell carcinoma (BCC), the most prevalent form of skin cancer, and cutaneous squamous cell carcinoma (cSCC), the second most common type. Both BCC and cSCC represent a significant health burden, particularly in immunocompromised individuals and the elderly. The immune system plays a pivotal role in the development and progression of NMSC, making it a critical focus for therapeutic interventions. This review highlights key immunological targets in BCC and cSCC, with a focus on immune checkpoint molecules such as PD-1/PD-L1 and CTLA-4, which regulate T cell activity and contribute to immune evasion. This review also highlights anti-tumor immune cell subsets within the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TILs) and dendritic cells. Additionally, it examines the immunosuppressive elements of the TME, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and cancer-associated fibroblasts (CAFs), as well as their roles in NMSC progression and resistance to therapy. Emerging strategies targeting these immune elements, such as monoclonal antibodies, are also discussed for their potential to enhance anti-tumor immune responses and improve clinical outcomes. By elucidating the immunological landscape of BCC and cSCC and drawing comparisons to melanoma, this review highlights the transformative potential of immunotherapy in treating these malignancies.

Contribution of Keratinocytes in Skin Cancer Initiation and Progression.

Keratinocytes are major cellular components of the skin and are strongly involved in its homeostasis. Oncogenic events, starting mainly from excessive sun exposure, lead to the dysregulation of their proliferation and differentiation programs and promote the initiation and progression of non-melanoma skin cancers (NMSCs). Primary melanomas, which originate from melanocytes, initiate and develop in close interaction with keratinocytes, whose role in melanoma initiation, progression, and immune escape is currently being explored. Recent studies highlighted, in particular, unexpected modes of communication between melanocytic cells and keratinocytes, which may be of interest as sources of new biomarkers in melanomagenesis or potential therapeutic targets. This review aims at reporting the various contributions of keratinocytes in skin basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma, with a greater focus on the latter in order to highlight some recent breakthrough findings. The readers are referred to recent reviews when contextual information is needed.

Tumor-Infiltrating T Cells in Skin Basal Cell Carcinomas and Squamous Cell Carcinomas: Global Th1 Preponderance with Th17 Enrichment-A Cross-Sectional Study.

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are high-incidence, non-melanoma skin cancers (NMSCs). The success of immune-targeted therapies in advanced NMSCs led us to anticipate that NMSCs harbored significant populations of tumor-infiltrating lymphocytes with potential anti-tumor activity. The main aim of this study was to characterize T cells infiltrating NMSCs. Flow cytometry and immunohistochemistry were used to assess, respectively, the proportions and densities of T cell subpopulations in BCCs (n = 118), SCCs (n = 33), and normal skin (NS, n = 30). CD8+ T cells, CD4+ T cell subsets, namely, Th1, Th2, Th17, Th9, and regulatory T cells (Tregs), CD8+ and CD4+ memory T cells, and γδ T cells were compared between NMSCs and NS samples. Remarkably, both BCCs and SCCs featured a significantly higher Th1/Th2 ratio (~four-fold) and an enrichment for Th17 cells. NMSCs also showed a significant enrichment for IFN-γ-producing CD8+T cells, and a depletion of γδ T cells. Using immunohistochemistry, NMSCs featured denser T cell infiltrates (CD4+, CD8+, and Tregs) than NS. Overall, these data favor a Th1-predominant response in BCCs and SCCs, providing support for immune-based treatments in NMSCs. Th17-mediated inflammation may play a role in the progression of NMSCs and thus become a potential therapeutic target in NMSCs.

Triterpenoid ursolic acid regulates the environmental carcinogen benzo[a]pyrene-driven epigenetic and metabolic alterations in SKH-1 hairless mice for skin cancer interception.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion and progression of non-melanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid (UA) regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic cytosines followed by guanine residues (CpG) methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine-rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamin metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate and thiamin metabolism during the promotion phase; and beta-alanine and pathothenate coenzyme A (CoA) biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC.

Exploring the impact of TGF-β family gene mutations and expression on skin wound healing and tissue repair.

Transforming Growth Factor-Beta (TGF-β) signalling pathway is of paramount importance in the processes of wound healing, epidermal integrity maintenance and development of skin cancer. The objective of this research endeavour was to clarify the impact of gene mutations and variations in expression within TGF-β family on mechanisms of tissue repair, as well as to identify potential targets for therapeutic purposes in non-melanoma skin cancer (NMSC). The methods utilized in this study involved obtaining RNA-seq data from 224 NMSC patients and paired normal skin tissues from the PRJNA320473 and PRJEB27606 databases. The purpose of the differential gene expression analysis was to identify genes whose expression had changed significantly. In order to evaluate the effects and interrelationships of identified gene variants, structural analysis with AlphaFold and PDB data and network analysis with the STRING database were both utilized. Critical gene expression was externally validated through the utilization of the GEPIA database. Tumour tissues exhibited a notable upregulation of genes associated with the TGF-β pathway, specifically MMP1, MMP3, MMP9, EGF, COL3A1 and COL1A2, in comparison with normal tissues. As indicated by the central node status of these genes in the network analysis, they play a crucial role in the progression of NMSCs. The results of the structural analysis suggested that mutations might cause functional disruptions. External validation of the upregulation confirmed the expression trends and emphasized the biomarker potential of the upregulated genes. In conclusion, this research offered thorough examination of molecular modifications that occur in TGF-β family genes, which are linked to cutaneous wound healing and NMSC. The modified expression of the identified hub genes may represent innovative targets for therapeutic intervention.

Progression of non-melanoma skin cancer cases in Brazil

Introduction: Skin cancer is a pathology of multifactorial etiology. BCC and SCC are often referred to as non-melanoma skin câncer and they are a health problem in Brazil due to their high incidence. Objective: Analyze the prevalence and progression of non-melanoma skin cancer, in Brazil, in a period between 2015 and 2020. Methods: It corresponds to a quantitative epidemiological study. Results: Meaningfully, compared to the year of 2015, 2020 had an increase of, approximately 1.800%. Conclusions: There has been a significant increase in the number of diagnoses of the disease in recent years, especially in the last 3 years, corroborating current studies about the country's concern with the advancing number of cases of BCC and SCC.

Serine and one-carbon metabolism sustain non-melanoma skin cancer progression

Non-melanoma skin cancer (NMSC) is a tumor that arises from human keratinocytes, showing abnormal control of cell proliferation and aberrant stratification. Cutaneous basal cell carcinoma (cBCC) and cutaneous squamous cell carcinoma (cSCC) are the most common sub-types of NMSC. From a molecular point of view, we are still far from fully understanding the molecular mechanisms behind the onset and progression of NMSC and to unravel targetable vulnerabilities to leverage for their treatment, which is still essentially based on surgery. Under this assumption, it is still not elucidated how the central cellular metabolism, a potential therapeutical target, is involved in NMSC progression. Therefore, our work is based on the characterization of the serine anabolism/catabolism and/or one-carbon metabolism (OCM) role in NMSC pathogenesis. Expression and protein analysis of normal skin and NMSC samples show the alteration of the expression of two enzymes involved in the serine metabolism and OCM, the Serine Hydroxy-Methyl Transferase 2 (SHMT2) and Methylen-ThetraHydroFolate dehydrogenase/cyclohydrolase 2 (MTHFD2). Tissues analysis shows that these two enzymes are mainly expressed in the proliferative areas of cBCC and in the poorly differentiated areas of cSCC, suggesting their role in tumor proliferation maintenance. Moreover, in vitro silencing of SHMT2 and MTHFD2 impairs the proliferation of epidermoid cancer cell line. Taken together these data allow us to link the central cellular metabolism (serine and/or OCM) and NMSC proliferation and progression, offering the opportunity to modulate pharmacologically the involved enzymes activity against this type of human cancer.

CYLD Inhibits the Development of Skin Squamous Cell Tumors in Immunocompetent Mice.

Cylindromatosis (CYLD) is a deubiquitinase (DUB) enzyme that was initially characterized as a tumor suppressor of adnexal skin tumors in patients with CYLD syndrome. Later, it was also shown that the expression of functionally inactive mutated forms of CYLD promoted tumor development and progression of non-melanoma skin cancer (NMSC). However, the ability of wild-type CYLD to inhibit skin tumorigenesis in vivo in immunocompetent mice has not been proved. Herein, we generated transgenic mice that express the wild type form of CYLD under the control of the keratin 5 (K5) promoter (K5-CYLDwt mice) and analyzed the skin properties of these transgenic mice by WB and immunohistochemistry, studied the survival and proliferating characteristics of primary keratinocytes, and performed chemical skin carcinogenesis experiments. As a result, we found a reduced activation of the nuclear factor kappa B (NF-κB) pathway in the skin of K5-CYLDwt mice in response to tumor necrosis factor-α (TNF-α); accordingly, when subjected to insults, K5-CYLDwt keratinocytes are prone to apoptosis and are protected from excessive hyperproliferation. Skin carcinogenesis assays showed inhibition of tumor development in K5-CYLDwt mice. As a mechanism of this tumor suppressor activity, we found that a moderate increase in CYLD expression levels reduced NF-κB activation, which favored the differentiation of tumor epidermal cells and inhibited its proliferation; moreover, it decreased tumor angiogenesis and inflammation. Altogether, our results suggest that increased levels of CYLD may be useful for anti-skin cancer therapy.

Investigation of IL-17A Serum Levels in Patients with Nonmelanoma Skin Cancer.

Background Role of interleukin 17A (IL-17A) in carcinogenesis and cancer growth is controversial. Although some researches support its antitumor activity, some others suggest that it promotes the growth and development of different types of cancer including skin cancer by activation of STAT3. Although the function of the cytokines such as IL-17A has been extensively studied in various types of cancer, nonmelanoma skin cancer (NMSC) has not received much attention. Therefore, the present study was aimed to investigate the serum levels of IL-17A in NMSC patients. Methods This cross-sectional study was performed on 60 patients with basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) as well as 57 age-sex matched healthy individuals as control group. Measurement of IL-17A serum levels in both case and control groups was performed by a commercially reliable sandwich enzyme-linked immunosorbent assay (ELISA) kit. Results In this study, we observed that IL-17A serum levels in NMSC patients were significantly higher than the control group (P < 0.001). Also, both BCC and SCC patients had higher levels of IL-17A in their sera in comparison to the controls (P=0.001 and P < 0.001, respectively). However, there was no significant difference between SCC and BCC patients regarding serum levels of IL-17A. Conclusion According to our results, it can be concluded that IL-17A may play a role in inducing the growth and progression of NMSC and it can be used as a therapeutic target in these patients in future.

The Impact of Notch Signaling for Carcinogenesis and Progression of Nonmelanoma Skin Cancer: Lessons Learned from Cancer Stem Cells, Tumor Angiogenesis, and Beyond.

Since many decades, nonmelanoma skin cancer (NMSCs) is the most common malignancy worldwide. Basal cell carcinomas (BCC) and squamous cell carcinomas (SCC) are the major types of NMSCs, representing approximately 70% and 25% of these neoplasias, respectively. Because of their continuously rising incidence rates, NMSCs represent a constantly increasing global challenge for healthcare, although they are in most cases nonlethal and curable (e.g., by surgery). While at present, carcinogenesis of NMSC is still not fully understood, the relevance of genetic and molecular alterations in several pathways, including evolutionary highly conserved Notch signaling, has now been shown convincingly. The Notch pathway, which was first developed during evolution in metazoans and that was first discovered in fruit flies (Drosophila melanogaster), governs cell fate decisions and many other fundamental processes that are of high relevance not only for embryonic development, but also for initiation, promotion, and progression of cancer. Choosing NMSC as a model, we give in this review a brief overview on the interaction of Notch signaling with important oncogenic and tumor suppressor pathways and on its role for several hallmarks of carcinogenesis and cancer progression, including the regulation of cancer stem cells, tumor angiogenesis, and senescence.

Significance of SOX18 expression in nonmelanoma skin cancers for prediction of high-risk patients: a preliminary study.

SOX18 is an integral transcription factor that is involved in endothelial cells differentiation during both angiogenesis and lymphangiogenesis. Therefore, it has been implicated in tumor progression and metastasis. To study SOX18 expression in nonmelanoma skin cancers (NMSCs) in comparison to seborrheic keratosis (SK) and normal control skin, and to assess its probable role in tumor evolution and progression. This study was conducted on 60 specimens of NMSCs: 30 basal cell carcinomas (BCC) and 30 squamous cell carcinomas (SCC), 30 specimens of SK, and 30 normal skin specimens. All were examined for immunohistochemical expression of SOX18 antibody. Additionally, morphometric assessment of vessel density (blood & lymphatic) in each specimen was estimated. Significant SOX18 overexpression was observed in all studied cutaneous tumors in comparison to control skin. The highest score of SOX18 expression was detected in SCC, then BCC, and the least expression was reported in SK with significant difference between them. Furthermore, significant upregulation of SOX18 expression was observed in high-risk types of both BCC and SCC compared to low-risk types. Stromal vessel density showed significant differences between the studied tumors with the highest mean value in SCC, followed by BCC and then SK. Positive correlation between SOX18 expression in the studied tumors and their vessel density was detected. SOX18 may have a potential role in the evolution as well as progression of NMSCs, possibly through induction of both angiogenesis and lymphangiogenesis. Furthermore, it could be beneficial for prediction of NMSC patients with poor prognosis.

Deficiency in fibroblast PPARβ/δ reduces nonmelanoma skin cancers in mice.

The incidence of nonmelanoma skin cancer (NMSC) has been increasing worldwide. Most studies have highlighted the importance of cancer-associated fibroblasts (CAFs) in NMSC progression. However much less is known about the communication between normal fibroblasts and epithelia; disruption of this communication affects tumor initiation and the latency period in the emergence of tumors. Delineating the mechanism that mediates this epithelial-mesenchymal communication in NMSC could identify more effective targeted therapies. The nuclear receptor PPARβ/δ in fibroblasts has been shown to modulate adjacent epithelial cell behavior, however, its role in skin tumorigenesis remains unknown. Using chemically induced skin carcinogenesis, we showed that FSPCre-Pparb/dex4 mice, whose Pparb/d gene was selectively deleted in fibroblasts, had delayed emergence and reduced tumor burden compared with control mice (Pparb/dfl/fl). However, FSPCre-Pparb/dex4-derived tumors showed increased proliferation, with no difference in differentiation, suggesting delayed tumor initiation. Network analysis revealed a link between dermal Pparb/d and TGF-β1 with epidermal NRF2 and Nox4. In vitro investigations showed that PPARβ/δ deficiency in fibroblasts increased epidermal Nox4-derived H2O2 production, which triggered an NRF2-mediated antioxidant response. We further showed that H2O2 upregulated NRF2 mRNA via the B-Raf-MEK1/2 pathway. The enhanced NRF2 response altered the activities of PTEN, Src, and AKT. In vivo, we detected the differential phosphorylation profiles of B-Raf, MEK1/2, PTEN, Src, and AKT in the vehicle-treated and chemicallytreated epidermis of FSPCre-Pparb/dex4 mice compared with that in Pparb/dfl/fl mice, prior to the first appearance of tumors in Pparb/dfl/fl. Our study revealed a role for fibroblast PPARβ/δ in the epithelial-mesenchymal communication involved in cellular redox homeostasis.

The Role of Classical and Novel Forms of Vitamin D in the Pathogenesis and Progression of Nonmelanoma Skin Cancers.

Nonmelanoma skin cancers including basal and squamous cell carcinomas (SCC and BCC) represent a significant clinical problem due to their relatively high incidence, imposing an economic burden to healthcare systems around the world. It is accepted that ultraviolet radiation (UVR: λ=290-400nm) plays a crucial role in the initiation and promotion of BCC and SCC with UVB (λ=290-320nm) having a central role in this process. On the other hand, UVB is required for vitamin D3 (D3) production in the skin, which supplies >90% of the body's requirement for this prohormone. Prolonged exposure to UVB can also generate tachysterol and lumisterol. Vitamin D3 itself and its canonical (1,25(OH)2D3) and noncanonical (CYP11A1-intitated) D3 hydroxyderivatives show photoprotective functions in the skin. These include regulation of keratinocyte proliferation and differentiation, induction of anti-oxidative responses, inhibition of DNA damage and induction of DNA repair mechanisms, and anti-inflammatory activities. Studies in animals have demonstrated that D3 hydroxyderivatives can attenuate UVB or chemically induced epidermal cancerogenesis and inhibit growth of SCC and BCC. Genomic and non-genomic mechanisms of action have been suggested. In addition, vitamin D3 itself inhibits hedgehog signaling pathways which have been implicated in many cancers. Silencing of the vitamin D receptor leads to increased propensity to develop UVB or chemically induced epidermal cancers. Other targets for vitamin D compounds include 1,25D3-MARRS, retinoic orphan receptors α and γ, aryl hydrocarbon receptor, and Wnt signaling. Most recently, photoprotective effects of lumisterol hydroxyderivatives have been identified. Clinical trials demonstrated a beneficial role of vitamin D compounds in the treatment of actinic keratosis. In summary, recent advances in vitamin D biology and pharmacology open new exciting opportunities in chemoprevention and treatment of skin cancers.

Deciphering the role of nuclear and cytoplasmic IKKα in skin cancer.

Nonmelanoma skin cancers (NMSC) are the most common human malignancies. IKKα is an essential protein for skin development and is also involved in the genesis and progression of NMSC, through mechanisms not fully understood. While different studies show that IKKα protects against skin cancer, others indicate that it promotes NMSC. To resolve this controversy we have generated two models of transgenic mice expressing the IKKα protein in the nucleus (N-IKKα mice) or the cytoplasm (C-IKKα mice) of keratinocytes. Chemical skin carcinogenesis experiments show that tumors developed by both types of transgenic mice exhibit histological and molecular characteristics that make them more prone to progression and invasion than those developed by Control mice. However, the mechanisms through which IKKα promotes skin tumors are different depending on its subcellular localization; while IKKα of cytoplasmic localization increases EGFR, MMP-9 and VEGF-A activities in tumors, nuclear IKKα causes tumor progression through regulation of c-Myc, Maspin and Integrin-α6 expression. Additionally, we have found that N-IKKα skin tumors mimic the characteristics associated to aggressive human skin tumors with high risk to metastasize. Our results show that IKKα has different non-overlapping roles in the nucleus or cytoplasm of keratinocytes, and provide new targets for intervention in human NMSC progression.

A conserved C-terminal sequence of high-risk cutaneous beta-human papillomavirus E6 proteins alters localization and signalling of β1-integrin to promote cell migration

Beta-human papillomaviruses (β-HPV) infect cutaneous epithelia, and accumulating evidence suggests that the virus may act as a co-factor with UV-induced DNA damage in the development and progression of non-melanoma skin cancer, although the molecular mechanisms involved are poorly understood. The E6 protein of cutaneous β-HPV types encodes functions consistent with a role in tumorigenesis, and E6 expression can result in papilloma formation in transgenic animals. The E6 proteins of high-risk α-HPV types, which are associated with the development of anogenital cancers, have a conserved 4 aa motif at their extreme C terminus that binds to specific PDZ domain-containing proteins to promote cell invasion. Likewise, the high-risk β-HPVs HPV5 and HPV8 E6 proteins also share a conserved C-terminal motif, but this is markedly different from that of α-HPV types, implying functional differences. Using binding and functional studies, we have shown that β-HPV E6 proteins target β1-integrin using this C-terminal motif. E6 expression reduced membrane localization of β1-integrin, but increased overall levels of β1-integrin protein and its downstream effector focal adhesion kinase in human keratinocytes. Altered β1-integrin localization due to E6 expression was associated with actin cytoskeleton rearrangement and increased cell migration that was abolished by point mutations in the C-terminal motif of E6. We concluded that modulation of β1-integrin signalling by E6 proteins may contribute towards the pathogenicity of these β-HPV types.

Expression and Function of Macrophage Migration Inhibitory Factor in the Pathogenesis of UV‐Induced Cutaneous Nonmelanoma Skin Cancer†

Chronic skin exposure to ultraviolet light stimulates the production of cytokines known to be involved in the initiation of skin cancer. Recent studies in mouse models suggested a role for macrophage migration inhibitory factor (MIF) in the UVB-induced pathogenesis of nonmelanoma skin cancer (NMSC). Our studies aimed at defining the pathophysiological function of MIF in cutaneous inflammatory reactions and in the development and progression of NMSC. Immunohistochemical analysis revealed a moderate expression of MIF in normal human skin samples but an enhanced expression of this cytokine in lesional skin of patients with actinic keratosis or cutaneous SCC. Enzyme-linked immunosorbent assay studies showed a time-dependent increase in MIF secretion after a moderate single-dose UVB irradiation in NHEKs and SCC tumor cells. MIF is known to interact with CXCR2, CXCR4 and CD74. These receptors are not constitutively expressed in keratinocytes and HaCaT cells and their expression is not induced by UVB irradiation either. However, stimulation with IFNγ upregulated CD74 surface expression in these cells. Affymetrix(®) Gene Chip analysis revealed that only keratinocytes prestimulated with IFNγ are responsive to MIF. These findings indicate that MIF may be an important factor in the pathogenesis of NMSC tumorigenesis and progression in an inflammatory environment.

Role of Matriptase and Proteinase-Activated Receptor-2 in Nonmelanoma Skin Cancer

Matriptase (membrane-type serine proteinase) was reported to play a role in nonmelanoma skin cancer progression. Moreover, it was shown to stimulate proteinase-activated receptor-2 (PAR(2)) in vitro. Hepatocyte growth factor activator inhibitor-1 (HAI-1), the matriptase inhibitor, is an important regulator of enzyme activity. Therefore, the aim of this study was to elucidate the putative role of matriptase, HAI-1, and PAR(2) in normal human skin, as well as in basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs). In normal human epidermis, PAR(2) colocalized with matriptase and HAI-1. Immunoreactivity of all proteins was found to be diminished in BCCs. Likewise, PAR(2) immunoreactivity was significantly decreased, whereas matriptase immunoreactivity was enhanced with SCC progression. We could also show that matriptase was complexed to HAI-1 in normal human skin, whereas in SCCs, the enzyme was present in an unassociated form. Both a specific peptide agonist for PAR(2) and the proteinase domain of matriptase were able to induce intracellular calcium mobilization and inhibition of proliferation in cultured HaCaT keratinocytes. In conclusion, our results suggest that PAR(2) is a substrate for matriptase in human skin in vivo. Deregulation of these proteins delineates SCC progression.

Macrophage migration inhibitory factor (MIF) plays a critical role in pathogenesis of ultraviolet‐B (UVB) ‐induced nonmelanoma skin cancer (NMSC)

Mounting evidence suggests that macrophage migration inhibitory factor (MIF) may serve as an important link between chronic inflammation and cancer development. The proinflammatory and proangiogenic activities of MIF position it as a potentially important player in the development and progression of nonmelanoma skin cancer (NMSC). To assess the role of MIF in the development and progression of NMSC, we exposed MIF(-/-) BALB/c mice to acute and chronic ultraviolet B (UVB) irradiation. Our studies demonstrate that MIF(-/-) BALB/c mice have a significantly diminished acute inflammatory response to UVB exposure compared to wild-type mice, as measured by myeloperoxidase activity, dermal neutrophil infiltration, and edematous response. Relative to wild-type mice, MIF(-/-) mice also show significantly lower vascular endothelial growth factor (VEGF) concentrations in whole skin and significantly lower 8-oxo-dG adduct concentrations in epidermal DNA following UVB exposure. Furthermore, MIF(-/-) mice showed significant increases in p53 activity, epidermal thickness, and epidermal cell proliferation following acute UVB insult. In response to chronic UVB exposure, MIF(-/-) mice showed a 45% reduction in tumor incidence, significantly less angiogenesis, and delayed tumor progression when compared to their wild-type counterparts. These data indicate that MIF plays an important role in UVB-induced NMSC development and progression.

Piecing Together p53

Inactivation of p53 by genetic or epigenetic means is a critical step in the pathogenesis of many cancers, including nonmelanoma skin cancers (NMSCs). Restoring the tumor-suppressor functions of mutant p53 is a theoretical approach to minimizing the progression of NMSC. Small-molecular-weight compounds capable of restoring wild-type p53 function therefore represent a novel approach to anti-oncogenesis. In a screen of more than 100,000 synthetic compounds, one agent — CP-31398 …

Genética molecular aplicada ao câncer cutâneo não melanoma

Os cânceres cutâneos não melanoma são as neoplasias malignas mais comuns em humanos. O carcinoma basocelular e o carcinoma espinocelular representam cerca de 95% dos cânceres cutâneos não melanoma, o que os torna um crescente problema para a saúde pública mundial devido a suas prevalências cada vez maiores. As alterações genéticas que ocorrem no desenvolvimento dessas malignidades cutâneas são apenas parcialmente compreendidas, havendo muito interesse no conhecimento e determinação das bases genéticas dos cânceres cutâneos não melanoma que expliquem seus fenótipos, comportamentos biológicos e potenciais metastáticos distintos. Apresenta-se uma revisão atualizada da genética molecular aplicada aos cânceres cutâneos não melanoma, em especial ao carcinoma basocelular e carcinoma espinocelular, enfatizando os mais freqüentes genes e os principais mecanismos de instabilidade genômica envolvidos no desenvolvimento dessas malignidades cutâneas.